1-hydrocarbylsulfonyl-2, 2-dichloro (ordialkoxy)-4, 5-imidazolidine diones



United States Patent 3,384,643 l-HYDROCARBYLSULFONYL-2,2-DICHLORO (0RDIALKOXY)-4,5-IMIDAZOLIDINE DIONES Adnan A. R. Sayigh, North Haven, andHenri Ulrich, Northford, Conn., assignors to The Upjohn Company,

Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Feb. 17,1965, Ser. No. 433,498 13 Claims. (Cl. 260-3095) ABSTRACT OF THEDISCLOSURE Novel l-alkylor aryl-sulfonyl-Z,2-dialkoxy-4,Simidazolidinediones are prepared by :alcoholysis of the corresponding 2,2-dichlorocompounds. The latter are also novel and obtained by reaction of oxalylchloride with the appropriately substituted sulfonylcarbodiimide. Thenovel 2,2-dia1koxy and 2,2-dichloro compounds are intermediates, byhydrolysis, for the corresponding sulfonylureas which have antidiabeticactivity.

This invention relates to novel intermediates in the production ofuseful, oral antidiabetics of the sulfonylurea type and is moreparticularly concerned with the production of l-alkylor l-arylsubstituted sulfonyl-2,2-dichloro- 3substituted-4,5-imidazolidinediones,l-alkylor aryl substituted sulfonyl-2,2-dialkoxy 3substituted-4,5-imidazolidinediones, :and a process for the productionthereof.

The novel compounds and the process of production thereof can beillustratively represented by the following formulae:

wherein R is selected from the group consisting of alkyl radicals havingfrom 1 to 6 carbon atoms, inclusive cycloalkyl radicals having from to 8carbon atoms, inclusive, phenyl, alkylphenyls in which the alkyl groupis defined as above, p-chlorophenyl, pacetylphenyl, p-alkoxy-,m-alkoxyand p,m-dialkoxypheny1 in which the alkyl radicals of the alkoxygroup are defined as hereinabove, wherein R is selected from alkylradicals defined as above, and the hexamethyleneimino radical, andwherein -R" is an alkyl group having from 1 to 4 carbon atoms,inclusive.

Examples of alkyl groups as herein described are, for R": methyl, ethyl,propyl, isopropyl, butyl, isobutyl; for R: the same as for R andadditionally pentyl, 1- methylbutyl, l-methylpropyl, hexyl,l-methylpentyl, 1- ethylbutyl and the like; for R: ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, l-methylbutyl, l-methylpropyl,lirfthylpentyl, hexyl, l-ethylbutyl, heptyl, octyl and the Examples ofcycloalkyls as used in this invention are ficlopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the Examples of aryl as herein used arephenyl, tolyl, 4- ethylphenyl, 4-propylphenyl, 4 butylphenyl, 4-hexylicephenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-ethoxyphenyl,3,4-dimethoxyphenyl, 4-hexyloxyphenyl, 4-acetoxyphenyl and the like.

The process of this invention comprises: treating a substitutedcarbodiimide of Formula I, above, with oxalyl chloride to obtain thecorresponding l-alkylor aryl-substituted sulfonyl-2,2-dich1oro-3substituted-4,5-imidazolidinedione (I I); and hydrolyzing Compound IIwith either water to give the corresponding 1,3-substituted parabanicacid (III) or a lower alkanol, such as methanol, ethanol, propanol, orbutanol, to give the corresponding 1,3-disubstituted-2,2-'dialkoxy-4,5imidazolidinedione of Formula IV.

The novel Compounds II and IV likewise as the compounds of Formula IIIare useful as intermediates for the production of sulfonylurea compoundsof the Formula V:

in which 'R and R have the same significance as above.

The compounds of Formula V are obtained by, for example, heatingl-alkylor aryl-substituted sulfonyl-2,2-dichloro-3-substituted-4,5-imidazolidinediones of Formula 11 with waterto give the substituted parabanic acids of Formula III which when heatedwith aqueous alkali give the sulfonylureas of Formula V. 1-alkyloraryl-substitute sulfonyl-2,2-dichloroas well as 2,2-dia1kylkoxy-3-substituted-4,S-imidazolidinediones of Formulae II and TV can also behydrolyzed with a mineral acid such a hydrochloric acid to give thesulfonylureas of structural Formula V. The sulfonylureas, particularlythose in which R is a substituted phenyl group, such as p-chloropheny-l,p-tolyl- (-p-methylphenyl), and in which R is alkyl, such as ethyl,propyl, n-butyl, hexamethyleneimino and the like, are importanthypoglycemic agents of which many are commercially used in the treatmentof diabetes mellitus.

The starting sulfonyl carbodiimides of this invention are generallyprepared by reacting arylsulfonylthioureas (Chem. Rev. 50, 146, 1952,and Ber. 83, 551, 1950) with an acid halide, for example, phosgene, inthe presence of an inert solvent under substantially anhydrousconditions at a temperature first between 0-60 and thereupon at a highertemperature, preferably between l50. Details of the methods ofproduction are further shown in the preparations.

In carrying out the process of the present invention, the selectedsulfonyl carbodiimide of Formula I is reacted with oxalyl chloride,preferably in a suitable solvent unreactive with oxalyl chloride andcarbodiimide. Such solvents are carbon tetrachloride, chloroform,methylene chloride, ethylene chloride, benzene, toluene, or the like,with carbon tetrachloride preferred. Equimolar amounts of sulfonylcarbodiimide (I) and of oxalyl chloride are preferably used in thisreaction but slightly smaller or larger than molar amounts of oxalylchloride per mole of carbodiimide are operative. The reaction can becarried out between 0 C. and the boiling point of the solvent, but ispreferentially carried out at room temperatures between 2030. Thereaction proceeds slowly and, at room temperature, 6 to 36 hours arerequired for the completion of the reaction. The desiredl-substitutedsulfonyl 2,2 dichlor0-3-substituted-4,S-imidazolidinedionethus obtained is isolated from the mixture by conventional procedures,e.g., by partial evaporation of the solvent and cooling. The materialwhich precipitates under these conditions is thereupon collected, andcan be purified by recrystallization or used in the crude form for thehydrolysis step with water to give the parabanic acid of Formula III orwith a lower alkanol to give the compounds of Formula IV. The variousmethods of hydrolysis are disclosed in detail in the subsequentexamples.

The following preparations and examples are illustrative of the processand products of the present invention, but are not to be construed aslimiting.

PREPARATION 1 N-phenylsulfonyl-N-ethylcarbodiimide To 9.76 g. (0.04mole) of N-phenylsulfonyl-N-ethylthiourea in 60 ml. of dry chlorobenzenewas added 4 g. (0.04 mole) of phosgene in 40 ml. of dry chlorobenzenedropwise with cooling and stirring over a period of 14 minutes at 5 C.After stirring for 90 minutes at 25 C., the reaction mixture was heatedto 132 C. for 50 minutes while nitrogen was passed through the reactionmixture. A small amount of solid material was removed by filtration andupon evaporation of the chlorobenzene 7.8 g. of crude product wasobtained. Distillation under reduced pressure produced 4 g. (47.6%) ofN-phenylsulfonyl-N- ethylcarbodiimide, B.P. 139144 C. (0.2 mm.).

Analysis.Calcd. for C H N O S: C, 51.41; H, 4.79; N, 13.32. Found: C,51.37; H, 4.80; N, 13.11.

In the same manner as shown above,

N-phenylsulfonyl-N-methylcarbodiirnide,N-phenylsulfonyl-N-propylcarbodiimide,N-phenylsulfonyl-N'-isopropylcarbodiirnide,N-phenylsulfonyl-N-isobutylcarbodiimide,N-phenylsulfonyl-N-pentylcarbodiin1ide,N-phenylsulfonyl-N-isopentylcar-bodiimide, andN-phenylsulfonyl-N'-hexylcarbodiimide are prepared by substitutingN-phenylsulfonyl-N-methylthiourea, N-phenylsulfonyl-N-propylthiourea,N-phenylsulfonyl-N-isopropylthiourea,N-phenylsulfonyl-N-isobutylthiourea, N-phenylsulfonyl-N-pentylthiourea,N-phenylsulfonyl-N-isopenty1thiourea, andN-phenylsulfonyl-N'-hexylthiourea, respectively, for N-phenylsulfonyl-N-ethylthiourea.

PREPARATION 2 N-(p-tolylsulfonyl -N-ethylcarbodiimide To 7.74 g. (0.03mole) of N-(p-tolylsulfonyl)-N-ethylthiourea in 50 ml. of drychlorobenzene was added 3 g. (0.03 mole) of phosgene in 30 ml. of drychlorobenzene dropwise with stirring and cooling over a period of 11minutes at 3-4 C. After stirring for 1 hour at tempera tures between2528 C., the reaction mixture was refluxed for 40 minutes with nitrogenpassing through the reaction miXture. Evaporation of the ehlorobenzenegave 6.6 g. of crude product which upon distillation under re ducedpressure produced pure N-(p-tolylsulfonyl)-N- ethylcarbodiimide, B.P.147151 C. (0.25 mm.) (in 40.2% yield).

Analysis.-Calcd. for C H N O S: C, 53.55; H, 5.39; N, 12.49; S, 14.30.Found: C, 53.56; H, 5.26; N, 12.62; S, 14.42.

In the same manner as shown above, -N-[(4-ethylpheny1)sulfonyl] Nethylcarbodiimide, N-[(3-propylphenyl)sulfonyl] N ethylcarbodiimide, andN [(4- butylphenyl)sulfonyl] N ethylcarbodiimide are prepared bysubstituting N [(4 ethylphenyl)sulfonyl]-N- ethylthiourea, N [(3propylphenyl)sulfonyl]-N-ethy1- thiourea, and N [(4butylphenyl)sulfony1]N'-ethylthiourea, respectively, forN-(p-tolylsulfonyl)-N'-ethylthiourea.

PREPARATION 3 N -phenylsulfonyl-N-butylcarbodiimide To 10.88 g. (0.04mole) of N-phenylsulfonyl-N-butylthiourea in ml. of chlorobenzene wasadded 3.9 g. (0.04 mole) of phosgene in 40 m1. of dry chlorobenzene dropwise with stirring and cooling over a period of 11 minutes at 3 C. Afterstirring for 70 minutes at temperatures between -28 C., the reactionmixture was refluxed for 80 minutes at 130-l32 C. while nitrogen waspassed through for the first minutes. A small amount of solid materialwas removed by filtration and evaporation of the solvent afforded 8.9 g.of crude product. Distillation under reduced pressure produced 3.8 g.(40%) of N- phenylsulfonyl N butylcarbodiimide, B.P. 15l155 C. (0.1mm.).

Analysis.Calcd. 01 C11H14N202S: C, H, N, 11.75. Found: C, 55.51; H,5.89; N, 11.70.

In the same manner as shown above, N-phenylsulfonyl- Ncyclopentylcarbodiirnide, N-pheny1sulfonyl-N'-cyclohexylcarbodiimide,N-phenylsulfonyl N cycloheptylcarbodiimide, and N-phenylsulfonyl Ncyclooctylcarbodiirnide are prepared by substituting N-phenylusulfonyl-N-cyclopentylthiourea, N-phenylusulfonyl-N-cyclohexylthiourea,N-phenylsulfonyl-N-cycloheptylthiourea and N-phenylsulfonyl-N-cyclooctylthiourea, respectively, for N-phenylsulfonyl-N-butylthiourea.

PREPARATION 4 N- (-p-tolylsulfonyl) -N-butylcarbodiimide To 13.44 g.(0.047 mole) of N-(p-tolylsulfouyl)-N- butylthiourea in 94 m1. of drychlorobenzene was added 4.7 g. (0.047 mole) of phosgene in 40 ml. of drychlorobenzene dropwise with stirring and ice cooling over a period of 11minutes at 4 C. After stirring for 10 minutes at about 40 C., nitrogenwas passed through the reaction mixture and the mixture was refluxed for70 minutes at 132 C. Evaporation of the chlorobenzene gave 12.3 g. ofcrude product. Distillation under reduced pressure produced 5.6 g.(47.3%) of N-(p-tolylsulfonyl)-N-butylcarbodiimide, B.P. 159-162 C. (0.2.mm.).

Analysis.Calcd. for C H N O S: C, 57.12; H, 6.38; N, 11.10; S, 12.70.Found: C, 56.36; H, 6.36; N, 11.05; S, 1317.

In the same manner as shown above,N-(p-tolylsulfonyl)-N-cyclopentylcarbodiimide, N (p-tolylsulfonyD-N-cyclohexylcarbomiide, N (p-tolyluslfonyl)-N-cycloheptylcarbodiimide, N(p tolylsulfonyl)-N-cyelooctylcarbodiimide, N-[ (4-ethylphenyl)sulfonyl] I-cyclohexylcarbodiimide, N [(4propylphenyl)sulfony1]-N'-cycloheptylcarbodiimide, and N-[(3-butylphenyl)sulfonyl]-N- cyclooctylcarbodiimide are prepared bysubstituting N- (p-tolylsulfonyl)-N-cyclopentylthiourea,N-(p-tolylsulfonyl)-N-cyclohexylthiourea, N (p tolylsu1fonyl)-N-cycloheptylthiourea, N (p-tolylsulfonyl)-N-cyclooctylthiourea, N [(4ethylphenyl)sulfonyl]-N-cyclohexylthiourea, N[(4-propy1pheny1)sulfonyl]-N-cycloheptylthiourea, andN-[(3-buty1phenyl)sulfonyl]-N-cyelooctylthiourea, respectively, forN-(p-tolylsulfonyl)-N-butylthiourea.

PREPARATION 5 N- (p-tolylsulfonyl) -N'-butylcarbodiirnide To 11.54 g.(0.04 mole) of N-(p-tolylsulfonyl)-N- butylthiourea suspended in 120 ml.of carbon tetrachloride was added 8.32 g. (0.04 mole) of prosphoruspentachloride. On heating at 35 C. evolution of hydrogen chloride wasobserved and the phosphorus pentachloride was consumed within 15 minutes(temperature 35-47 C.). The reaction mixture was refluxed at 7778 C. for5 hours and on evaporation of the solvent and distillation under reducedpressure produced 7.7 g. (75.5%) ofN-(p-tolylsulfonyl)-N-butylcarbodiirnide, B.P. -186 C. 1.3 mm.).

In the same manner as shown above, N-[(3,4-dimethylphenyl)-sulfonyl]-N-butylcarbodiimide, N [(3- chloro 4methylphenyl)sulfonyl] N propylcarbodiimide, N [(3ethyl-4-ethypheny1)sulfonyl]-N-propy1- carbodiimide, andN-[(3-chloro-4-rnethoxyphenyl)-sulfonyl]-N-piperidinocarbodiimide areprepared by substituting N [(3,4 dimethylphenyl)sultonyl] Nbutylthiourea, N [(3 chloro-4-methylphenyl)sulfonyl]-N'- propylthiourea,N [(3-ethyl-4-ethoxyphenyl)-sulfonyi]-N'-[(3-chloro-4-methoxypl1enyl)sulfonyl] N piperidinothiourea forN-(p-tolylsulfonyl)-N-butylthiourea.

7 sulfonyl-N-ethylcarbodiimide was treated with oxalyl chloride incarbon tetrachloride solution to givel-phenylsulfonyl-Z,2-dichloro-3-ethyl-4,S-imidazolidinedione.

EXAMPLE 4 1-phenylsulfonyl-2,2-dichloro-3-n-propyl-4,5-imidazolidinedione In the manner given in Example 1, N-phenylsulfonyl-N'-n-propylcarbodiimide is reacted with oxalyl chloride in carbontetrachloride solution to give l-phenylsulfonyl-2,2-dichloro-3-n-propyl-4,S-imidazolidinedione.

EXAMPLE 5 1-phenylsulfony1-2,2-dichloro-3-n-pentyl-4,5-imidazolidinedione In the manner given in Example 1, N-phenylsulfonyl-N-n-pentylcarbodiimide is reacted with oxalyl chloride in carbontetrachloride solution to give l-phenylsulfonyl-2,2-dichloro-3-n-pentyl-4,S-imidazolidinediOne.

EXAMPLE 6 l-(p-tolylsulfonyl)-2,2-dichloro-3-ethyl-4,5-imidazolidinedione In the manner given in Example 1, N-(p-tolylsulfonyD-N'-ethylcarbodiimide was reacted with oxalyl chloride in carbontetrachloride solution to givel-(p-tolylsulfonyl)-2,2-dichloro-3-ethyl-4,S-imidazolidinedione.

EXAMPLE 7 l-[ (4-11-butylphenyl) sulfonyl] -2,2-dichloro-3-ethyl-4,5-imidazolidinedione In the manner given in Example 1,N-[4-n-butylphenyl)sulfonyl]-N-ethylcarbodiirnide was reacted withoxalyl chloride in carbon tetrachloride solution to give l-[(4- nbutylphenyDsulfonyl] 2,2 dichloro 3 ethyl 4,5- imidazolidinedione.

EXAMPLE 8 1-[ 3-n-propylphenyl sulfonyl] -2,2-dichloro-3- ethyl-4,S-imidazolidinedione In the manner given in Example 1,N-[(3-n-propylphenyl)sulphonyl]N-ethylcarbodiimide was reacted withoxalyl chloride in carbon tetrachloride solution to give 1- [(3 npropylphenyDsulfonyl] 2,2 dichloro 3- ethyl-4,5-imidazolidinedione.

EXAMPLE 9 1- (p-tolylsulfonyl)-2,2-dichloro-3-n-propyl-4,5-imidazolidinedione In the manner given in Example 1,N-(p-tolylsu1fonyl)- N'-n-propylcarbodiimide was reacted with oxalylchloride in carbon tetrachloride solution to give l-(p-tolylsulfonyl)2,2 dichloro 3 n propyl 4,5 imidazolidinedione.

EXAMPLE 10 1- (p-tolylsulfonyl -2,2-dichloro-3-cyclopentyl-4,5-imidazolidinedione In the manner given in Example 1,N-(p-tolylsulfonyD- N-cyclopentylcarbodiimide was reacted with oxalylchloride in carbon tetrachloride solution to give l-(p-tolylsulfonyl)2,2 dichloro 3 cyclopentyl 4,5 imidazolidinedione.

EXAMPLE 11 1- (p-tolylsulfonyl -2,2-dichloro-3-cyclooctyl-4,5-imidazolidinedione In the manner given in Example 1,N-(p-tolylsulfonyD- N'-cyclooctylcarbodiirnide was reacted with oxalylchloride in carbon tetrachloride solution to give l-(p-tolylsulfonyl)2,2 dichloro 3 cyclooctyl 4,5 imidazolidinedione.

EXAMPLE 12 1- (p-tolylsulfonyl 2,2-dichloro-3 -hexamethylene-irnino-4,5-imidazolidinedione In the manner given in Example 1, N-(p-tolylsulfonyl)- N'-hexamethyleneiminocarbodiimide was reacted withoxalyl chloride in carbon tetrachloride solution to give 1 (ptolylsulfonyl) 2,2 dichloro 3hexamethyleneirnino-4,5-imidazolidinedione.

EXAMPLE 13 1- (4-chlorophenyl) sulfonyl] 2,2-dichloro-3 -n-propyl-4,5-imidazolidinedione In the manner given in Example 1,N-[(4-chlorophenyl)sulfonyl]-N'-n-propylcarbodiimide was reacted withoxalyl chloride in carbon tetrachloride solution to give 1[(4-chlorophenyl)sulfonyl] 2,2 dichloro 3-n-propyl-4,S-imidazolidinedione.

EXAMPLE 14 l- (4-chlorophenyl sulfonyl]2,2-dichloro-3-cycloheptyl-4,S-imidazolidinedione In the manner given inExample 1, N-[(4-chlorophenyl sulfonyl -N-cycloheptylcarbodiimide wasreacted with oxalyl chloride in carbon tetrachloride solution to give 1[(4 chlorophenyl) sulfonyl] 2,2 dichloro-3-cycloheptyl-4,S-imidazolidinediones.

EXAMPLE 15 1-[ (4-bromophenyl sulfonyl] 2,2-dichloro-3-cyclohep tyl-4,5-imid azolidine dione In the manner given in Example 1,N-[(4-bromophenyl)sulfonyl]-N-cycloheptylcarbodiimide was reacted withoxalyl chloride in carbon tetrachloride solution to give 1 [(4bromophenyl)sulfonyl] 2,2 dichloro-3-cycloheptyl-4,S-imidazolidinediones.

EXAMPLE 16 1- 4-chloropheny1) sulfonyl]-2,2-dichloro-3-hexamethyleneimino-4,S-imidazolidinedione In the mannergiven in Example 1, N-[(4-chlorophenyl)sulfonyl] Nhexarnethyleneiminocarbodiimide was reacted with oxalyl chloride incarbon tetrachloride solution to give 1- [(4 chlorophenyl)sulfonyl] 2,2-dichloro 3 hexamethyleneirnino 4,5 imidazolidinedione.

EXAMPLE 17 l- (4-acetylphenyl sulfonyl-2,2-dichloro-3-cyclohexyl-4,S-imidazolidinedione In the manner given inExample 1, N-[(4-acetylphenyl) sulfonyl]-N-cyclohexylcarbodiimide wasreacted with oxalyl chloride in carbon tetrachloride solution to give 1[(4 acetylphen-yDsulfonyl] 2,2 dichloro 3 cyclohexyl-4,5imidazolidinedione.

EXAMPLE 18 1- (4-acetylphenyl sulfonyl]-2,2-dichloro-3-hexamethyleneimino-4,S-imidazolidinedione In the mannergiven in Example 1, N-[(4-acetylphenyl) sulfonyl] Nhexamethyleneiminocarbodiimide was reacted with oxalyl chloride incarbon tetrachloride solution to give 1 [(4 acetylphenyhsulfonyl] 2,2-dichloro 3 hexamethyleneimino 4,5 irnidazolidinedione.

EXAMPLE 19 1 (4-butyrylphenyl) sulfonyl] -2,2-dichloro-3-propy1-4,5-imidazolidinedione In the manner given in Example 1, N- [(4butyrylphenyl)sulfonyl]-N'-propylcarbodiimide was reacted with oxalylchloride in carbon tetrachloride solution to give 1 [(4butyrylphenyDsulfonyl] 2,2 dichloro 3- propyl-4,S-imidazolidinedione.

EXAMPLE 20 1- (4-hexanoylphenyl) sulfonyl 1 2,2-dichloro-3-n-butyl-4,5-imidazolidinedione In the manner given in Example 1,N-[(4-hexanoylphenyl sulfonyl] -N'-n-butylcarbodiimide was reacted withoxalyl chloride in carbon tetrachloride solution to give 1 [(4 hexanoylphenyl)sulfonyl] 2,2 dichloro-3-n-butyl 4,5-imidazolidinedione.

EXAMPLE 21 1-methylsulfonyl-2,2-dichloro-3-n-propyl-4,5-imidazolidinedione To a mixture of 0.81 g. (0.005 mole) ofl-methylsulfonyl-3-n-propylcarbodiimide in 8 ml. of carbontetrachloride, 0.635 g. (0.005 mole) of oxalyl chloride in 6 ml. ofcarbon tetrachloride was added. Upon standing for 20 hours 1.2 g.(83.3%) of crude material was obtained which, after recrystallizationfrom carbon tetrachloride, gave pure 1 methylsulfonyl 2,2 dichloro 3npropyl-4,5-imidazolidinedione of MP. 128 C.

In the manner given in Example 1, other l-alkylorarylsubstituted-s11lfonyl-2,2-dichloro 3 substituted-4,5-imidazolidinediones can be prepared by reacting selectedN-substituted-alkylor aryl-substituted-sulfonyl-N-substituted-carbodiimides with oxalyl chloride in a solvent inert tothe reactants. Representative imidazolidinediones thus obtained include1-phenylsulfonyl-2,2-dichloro-3-n-butyl-4,5-

imidazolidinedione,

1-pheny1sulfonyl-2,2-dichloro-3-isopropyl-4,5-

imidazolidinedione,

1-phenylsulfonyl-2,2-dichloro-3-isopentyl-4,5-

imidazolidinedione,

1-phenylsulfonyl-2,2-dichloro-3-n-hexy1-4,5-

imidazolidinedione,

1-[ (4-ethylphenyl) sulfonyl] -2,2-dichloro-3-ethyl- 4,5-imidazolidinedione 1-phenylsulfonyl-Z,2-dichloro-3 -cyclohexyl-4,

imidazolidinedione,

1-phenylsulfonyl-2,2-dichloro-3-cyclooctyl-4,5-

imid azolidinedione,

1- (p-tolylsulfonyl) -2,2-dichloro-3-cycloheptyl-4,5-

imidazolidinedione,

1-[ (4-propylphenyl sulfonyl] -2,2-dichloro-3 -cycloheptyl- 4,S-imidazolidinedione,

1- (4-ch1o1'ophenyl -su1fony1] -2,2-dichloro-3 -butyl- 4, 5 -imidazolidinedione,

1-[ (4-chlorophenyl sulfonyl] -2,2-dichloro-3-piperidino- 4, 5-imidazolidinedione,

1-[ (4-propylphenyl) sulfonyl] -2,2-dichloro-3-butyl-4,5-imidazolidinedione,

1- (4-bromophenyl sulfonyl] -2,2-dichloro-3-cycloheptyl-4,5-imidazolidinedione,

1-[ (3-meth0xyphenyl) sulfonyl] -2,2-dichloro-3- pro pyl-4,S-imidazolidinedione,

1- (3,4-dimethoxyphenyl sulfonyl] -2,2-dichloro 3 -n-p entyl-4, 5-imidazolidinedione,

1- (4-acetylphenyl sulfonyl] -2,2-dichloro-3-cycloheptyl- 4, 5-imidazo1idinedione,

1-methanesulfonyl-2,2-dichloro-3-n-butyl-4,5-

irnidazolidinedione,

1-ethylsulEonyl-Z,2-dichloro-3 -ethyl-4,5-

irnidazolidinedione,

1-n-butylsulfonyl-2,2-dichloro-3-cyclohexyl-4,5-

imidazolidinedione,

10 1-n-hexanesu1fony1-2,Z-dichloro-3-n-butyl-4,5-

imidazolidinedione, 1-cyclohexanesulfonyl-Z,2-dichloro-3-n-butyl-4,5-

imidazolidinedione, 1-cyclopentar1esulfonyl-2,2-dichloro-3-propyl-4,5-

imidazolidinedione,

and the like.

EXAMPLE 22 l-(p-tolylsulfonyl)-3-n-butyl parabanic acid To 0.38 g.(0.001 mole) of 1-(p-tolylsulfonyl)-2,2-dichloro-3-n-butyl-4,S-imidazolidinedione in 5 ml. of acetone a fewdrops of water was added and the reaction mixture was refluxed for 5minutes. Addition of water precipitated the parabanic acid derivative(melting point -127 C.). The crude material was recrystallized frombenzene-ligroin to give l-(p-tolylsulfonyl)-3-n-butyl parabanic acid in92.5% yield and of a melting point of 128 C.

Analysis. Calcd. for C H N O S: C, 51.84; H, 4.96; N, 8.63. Found: C,51.41; H, 4.92; N, 8.82.

EXAMPLE 23 1-(p-tolylsulfonyl)-3-ethy1 parabanic acid In the mannergiven in Example 22, l-(p-tolylsulfonyD- 2,2-dichloro 3ethyl-4,5-imidazolidinedione was hydrolyzed in acetone with a very smallamount of water (0.3 ml. in 8 ml. of water) to give l-(p-tolylsulfonyll-3-ethyl parabanic acid.

EXAMPLE 24 1-pheny1sulfonyl-3-n-butyl parabanic acid In the manner givenin Example 22, 1-phenylsulfonyl- 2,2-dichloro-3-n-butyl 4,5imidazolidinedione was hydrolyzed to give 1-phenylsulfonyl-3-n-butylparabanic acid.

EXAMPLE 25 1-phenylsulfonyl-3-ethyl parabanic acid In the manner givenin Example 22, l-phenylsulfonyl- 2,2-dichloro-3-ethyl 4,5imidazolidinedione was hydrolyzed to give 1-phenylsulfonyl-3-ethylparabanic acid.

EXAMPLE 26 1-phenylsulf0nyl-3-isobuty1 parabanic acid In the mannergiven in Example 22, 1-phenysulfonyl- 2,2-dichloro 3isobutyl-4,5-imidazolidinedione was hydrolyzed to give1-phenylsulfonyl-3-isobutyl parabanic acid.

EXAMPLE 27 1-phenylsulfonyl-3-n-propyl parabanic acid In the mannergiven in Example 22, l-phenylsulfonyl- 2,2-dichloro-3-n-propyl 4,5imidazolidinedione was hydrolyzed to give 1-phenylsulfonyl-3-n-propylparabanic acid.

EXAMPLE 28 l-phenylsulfonyl-3-n-pentyl parabanic acid In the mannergiven in Example 22, l-phenylsulfonyl- 2,2-dichloro-3-n-pentyl 4,5imidazolidinedione was hydrolyzed to give 1-phenylsulfonyl-3-n-pentylparabanic acid.

EXAMPLE 29 l-[(4-butylphenyl)sulfonyl1-3-ethyl parabanic acid In themanner given in Example 22, 1-[(4-butylphenyl) sulfonyl]-2,2-dimethyl 3ethyl-4,S-imidazolidinedione was hydrolyzed to give1-[(4-butylphenyl)sulfonyl] 3- ethyl parabanic acid.

1 EXAMPLE 30 1-(p-tolylsulfonyl)-3-n-propy1 parabanic acid In the mannergiven in Example 22, 1-(p-to1ylsulfonyl)-2,2-dich1oro-3-n-propyl-4,S-imidazolidinedione was hydro- 1 1 lyzed togive l-(p-tolylsulfonyl)-3-n-propyl parabanic acid.

EXAMPLE 31 l-(p-tolylsulfonyl)-3-cyclopentyl parabanic acid In themanner given in Example 22, l-(p-tolylsulfonyD-2,2-dichloro-3-cyclopentyl 4,5 imidazolidinedione was hydrolyzed to give1- (p-tolylsulfonyl)-3-cyclopentyl parabanic acid.

EXAMPLE 32 1-(p-tolylsulfonyl)-3-cyclooctyl parabanic acid In the mannergiven in Example 22, 1-(p-tolylsulfonyl)- 2,2-dichloro-3-cyclooctyl 4,5imidazolidinedione was hydrolized to give 1 (p-tolylsulfonyl) 3cyclooctyl parabanic acid.

EXAMPLE 33 l-(p-tolylsulfonyl)-3-hexamethyleneimino parabanic acid Inthe manner given in Example 22, l-(p-tolylsulfonyl)-2,2-dichloro-3-hexamethyleneimino 4,5 imidazolidinedione was hydrolyzedto give 1-(p-tolylsulfonyl)-3-hexamethyleneimino parabanic acid.

1- (4-chlorophenyl sulfonyl] -3 -hexamethyleneimino parabanic acid Inthe manner given in Example 22, 1-[(4-chlorophenyl)sulfonyl] 2,2dichloro-3-hexamethyleneimino-4,5- imidazolidinedione was hydrolyzed togive 1-[(4-chlorophenyl)sulfonyl]-3-hexamethyleneimin0 parabanic acid.

EXAMPLE 38 1-[ (4-acetylpheny1) sulfonyl] 3-cyclohexyl parabanic acid Inthe manner given in Example 22, l-{(4-acetylphenyl)sulfonyl] 2,2dichloro 3cycloheXyl-4,S-imidazolidinedione was hydrolyzed to givel-[(4-acetylphenyl) sulfonyl] -3-cyclohexyl parabanic acid.

EXAMPLE 39 1- (4-acetylphenyl sulfonyl] -3 -hexamethyleneimino parabanicacid In the manner given in Example 22, 1-[(4-acetylphenyl)sulfnyl] 2,2dichloro-3-hexamethyleneimino-4,5- imidazolidinedione was hydrolyzed togive 1-[(4-acetylphenyl)sulfonyl]-3-hexamethyleneimino parabanic acid.

EXAMPLE 40 1-[(4-butyrylphenyl)sulfonyl]-3-n-propyl parabanic acid Inthe manner given in Example 22, 1-[(4-butyrylphenyl)sulfonyl] 2,2dichloro-3-n-propyl-4,5-imidazolidine- 12 dione was hydrolyzed to give1-[(4-butyrylphenyl)sulfonyl]-3-n-propyl parabanic acid.

EXAMPLE 41 1-[(4-hexanoylphenyDsulfonyl] -3-n-butyl parabanic acid Inthe manner given in Example 22, l-[(4-hexanoylphenyl)sulfonyl] 2,2dichloro-3-n-butyl-4,5-imidazolidinedione was hydrolyzed to give1-[(4-hexanoylphenyl) sulfonyl]-3-n-butyl parabanic acid.

EXAMPLE 42 1-(p-tolylsulfonyD-Z,2-dimethoxy-3 -ethyl-4,5-imidazolidinedione A quantity of 1.4 g. ofl-(p-tolylsulfonyl)-2,2dichloro- 3-ethyl-4,S-imidazolidinedione wasdissolved in 8 ml. of methanol to which was added 0.3 ml. of water. Thesolution was refluxed for 5 minutes. The mixture was then cooled to roomtemperature and 20 m1. of ice-Water was added causing crudel-(p-tolylsulfonyl)-2,2-dimethoxy-3- ethyl-4,S-imidazolidinedione toprecipitate. The thus-obtained crude product was recrystallized frombenzeneligroin to give pure l-(p-tolylsulfonyl)-2,2-dimethoXy-3-ethyl-4,S-imidazolidinedione of melting point 126128 C.

Analysis.-Calcd. for C H N O S: N, 8.18. Found: N, 8.68.

EXAMPLE 43 l-phenylsulfonyl-2,2 dimethoxy-3-n-butyl-4,5-imidazolidinedione In the manner given in Example 42, l-phenylsulfonyl-2,2-dichloro-3-n-butyl-4,S-imidazolidinedione was hydrolyzed in methanolcontaining a small amount of water to give l-phenylsulfonyl 2,2dimethoXy-3-n-butyl-4,5-imidazolidinedione of melting point l02l04 C.

Analysis.Calcd. for 'C H N O S: C, 50.54; H, 5.65; N, 7.85. Found: C,50.68; H, 5.09; N, 7.97.

EXAMPLE 44 l-(p-tolylsulfonyl)-2,2-dimethoxy3-n-hutyl4,5-imidazolidinedione In the manner given in Example 42, 1-(p-tolylsulfonyD- 2,2-dichloro-3-n-butyl-4,S-imidazolidinedione washydrolyzed in methanol containing a small amount of water to give1-(p-tolylsulfonyl)-2,2 dimethoXy-3-nbutyl-4,5- imidazolidinedione.

EXAMPLE 45 l-(p-tolylsulfonyl)-2,2-diethoXy-3-n-butyl-4,5-imidazolidinedione In the manner given in Example 42,l-(p-tolylsulfonyD- 2,2-dichloro-3-n-buty1-4,S-imidazolidinedione washydrolyzed in ethanol containing a small amount of water to givel-(p-tolylsulfonyl) 2,2-diethoxy-3-n-butyl-4,5-imidazolidinedione.

EXAMPLE 46 1- (p-tolylsulfonyl)-2,2-dibutoxy-3-n-hutyl-4,5-imidazolidinedione In the manner given in Example 42,1-(p-tolylsulfonyl)- 2,2-dichl0ro-3-n-butyl-4,S-imidazolidinedione washydrolyzed in n-butanol containing a small amount of water to give1-(p-tolylsulfonyl)-2,2-dibutoXy-3-n-butyl-4,5-imidazolidinedione.

EXAMPLE 47 1- (4-n-butylphenyl)sulfonyl] -2,2-diethoxy-3-ethyl-4,5-imidazolidinedione In the manner given in Example 42,1-[(4-n-butylphenyl)sulfonyl] 2,2 diethoxy 3 ethyl 4,5imidazolidinedione was hydrolyzed in ethanol containing a small amountof water to give l-[(4-n-butylphenyl)sulfonyl] 2,2 diethoxy 3 ethyl 4,5imidazolidinedione.

EXAMPLE 48 1-(6-tolylsulfonyl)-2,2-dipropoxy-3-hexarnethyleneimino-4,5-imidazolidinedione In themanner given in Example 42, l-(p-tolylsulfonyl- 2,2 dichloro 3 nhexamethyleneimino 4,5 imidazolidinedione was hydrolyzed in propanolcontaining a small amount of water to give 1-(p-tolylsulfonyl)-2,2-diprpoxy-3-hexamethyleneimino-4,5-imidazolidinedione.

EXAMPLE 49 1-[ (4-chlorophenyl) sulfonyl] -2,2-diethoxy-3-n-propyl- 4,5-imidazolidinedione In the manner given in Example 42,1-[(4-chlorophenyl)sulfonyl] 2,2 dichloro 3 n propyl 4,5-imidazolidinedione was hydrolyzed in ethanol containing a small amountof water to give 1-[(4-chlorophenyl)sulfonyl] 2,2 diethoxy 3 n propyl4,5 imidazolidinedione.

EXAMPLE 50 1- (4-bromophenyl) sulfonyl]-2,2-dimethoxy-3-cycloheptyl-4,S-imidazolidinedione In the manner givenin Example 42, l-[(4-brornophenyl)sulfonyl] 2,2 dichloro 3 cycloheptyl4,5 imidazolidinedione was hydrolyzed in methanol containing a smallamount of water to give 1-[(4-bromophenyl)sulfonyl] 2,2 dimethoxy 3cycloheptyl 4,5 imidazolidined'ione.

EXAMPLE 51 1- (4-acetylphenyl sulfonyl] -2,2-diethoxy-3-cyclo-hexyl-4,5-imidazolidinedione In the manner given in Example 42,1-[(4-acetylphenyl)sulfonyl] 2,2 dichloro 3 cyclohexyl 4,5imidazolidinedione was hydrolyzed in ethanol containing a small amountof water to give 1-[(4-acetylphenyl)sulfonyl] 2,2 diethoxy 3 cyclohexyl4,5 imidazolidinedione.

In the manner given in Example 22, other l-alkyloraryl-substituted-sulfonyl 2,2 dialkoxy 3 substituted- 4,5-imidazolidinediones can be prepared by hydrolyzing the correspondingl-alkylor aryl-substituted-2,2-dichloro-3-substituted-4,5-imidazolidinediones in a lower alkanolcontaining from 1 to 4 carbon atoms, inclusive, containing a lowpercentage of water. Representative 1- alkyloraryl-substituted-2,2-dialkoxy-3-substituted 4,5- imidazolidinedionesthus obtained include 1- (4-phenyl) sulfonyl] -2,2-dipropoxy-3-ethyl-4,5

imidazolidinedione,

1-[ (4-phenyl sulfonyl] -2,2-diethoxy-3-isobutyl-4,5-

imidazolidinedione,

1-[ (4-phenyl) sulfonyl] -2,2-diethoxy-3-pentyl-4,5-

imidazolidinedione,

1- (p-tolylsulfonyl) -2,2-dipropoxy-3-ethyl-4,5 -imidazolidinedione,

1-[ (3 -propylphenyl) sulfonyl] -2,2-dipropoxy-3-ethyl-4,5-imidazolidinedione,

1- (p-tolylsulfonyl) -2,2-diisopr0poxy-3 -propyl-4,5-

imidazolidinedione,

1- p-tolylsulfonyl -2,2-diethoxy-3-cyclohexyl-4,5-

imidazolidinedione,

1- p-tolylsulfonyl) -2,2-dimethoxy-3-cyclopentyl-4,5-

imidazolidinedione,

1 p-tolylsulfonyl) -2,2-isobutyloxy-3 -hexamethyleneimino-4,5-imidazolidinedione,

1-[ (4-chlorophenyl) sulfonyl] -2,2-dimethoxy-3-cycloheptyl-4,5-imidazolidinedione,

1-[ (4-chlorophenyl sulfonyl] -2,2-propoxy-3-hexamethyleneimino-4,S-imidazolidinedione,

1- (4-acetylphenyl) sulfonyl]-2,2-diethoxy-3-hexamethyleneimino-4,S-imidazolidinedione,

1-[ (4-butyrylphenyl) sulfonyl] -2,2-diethoxy-3 -propyl- 4,5-imidazolidinedione,

1 4 1- 4-ethylphenyl) sulfonyl] -2,2-dimethoxy-3 -ethyl-4,5

imidazolidinedione,1-methanesulfonyl-Z,2-diethoxy-3-n-butyl-4,5-imidazolidinedione,1-n-butylsulfonyl-2,2-dipropoxy-3-cyclohexyl-4,5-imidazolidinedione,1-cyclohexylsulfonyl-2,2-diethoxy-3-n-butyl-4,5-imidazolidinedione,

and the like.

EXAMPLE 52 N- (p-tolylsulfonyl) -N-n-butylurea 1 g. ofl-(p-tolylsulfonyl)-3-n-butyl parabanic acid was hydrolyzed by heatingfor a period of 1 hour on a water bath in a solution consisting of 10ml. ethanol, 1 ml. Water and 0.5 g. of sodium hydroxide. The mixture wasthen cooled filtered, the filtrate was neutralized with dilutehydrochloric acid and the thus-precipitated, crude N-(p-tolylsulfonyl)-N'-n-butylurea was recrystallized from ethanol to givepure N-(p-tolylsulfonyl)-N-n-butylurea- [tolbutamide] EXAMPLE 53 N-[(pchlorophenyl) sulfonyl] -N'-n-propylurea In the same manner given inExample 52, 1-[(p-ch1orophenyl)sulfonyl1-3-n-propyl parabanic acid washydrolyzed with sodium hydroxide to give N-[(p-chlorophenyl) sulfonyl]-N'-n-propylurea.

In the manner given in Example 52, other l-arylsulfonyl andalkylsulfonyl-3-substituted parabanic acids can be converted to thecorresponding N-arylsulfonyl-N-substituted ureas which are presentlyused for the treatment of diabetes mellitus.

EXAMPLE 54 N- p-tolylsulfonyl -N'-n-butylurea A solution of 1 g. of1-(p-tolylsulfonyl)-2,2-dimethoxy- 3-n-butyl-4,S-imidazolidinedione wasrefluxed for 1 hour in a mixture containing 10 ml. ethanol, 1 ml. ofconcentrated hydrochloric acid and 1 ml. of water. Thereafter, themixture was cooled to room temperature and 15 m1. of 1 N hydrochloricacid was added. A precipitate of N- (p-tolylsulfonyl)-N-n-butylurea wasrecovered from the mixture by filtration, and purified further bydissolution in ammonia aqueous solution and reprecipitation withhydrochloric acid.

In the manner given in Example 54, other N-aryl-N'- substituted ureacompounds having hypoglycemic activity can be produced by hydrolyzingwith a mineral acid, particularly hydrochloric acid, the correspondingl-alkylor aryl-substituted-sulfonyl-Z,2-dichloroor 2,2-dialkoxy-4,5-imidazolidinedione.

We claim:

1. A l substituted-sulfonyl-2,2-dichloro-4,S-imidazolidindione of theformula:

wherein R is selected from the group consisting of alkyl of from 1 to 6carbon atoms, inclusive, cycloalkyl of from 5 to 8 carbon atoms,inclusive, phenyl, alkylphenyl in which the alkyl is defined as above,p-chlorophenyl, pacetylphenyl, p-alkoxyphenyl, m-alkoxyphenyl andp,mdialkoxyphenyl, in which the alkyl of the alkoxy group is defined ashereinabove, and wherein R is selected from the group consisting ofalkyl of from 2 to 8 carbon atoms, inclusive, cycloalkyl defined asabove, and hexamethyleneimino.

' 2. 1 (p tolylsulfonyl) 2,2 dichloro 3 n butyl- 4,5-imidazolidinedione.

3. 1 (p tolylsulfonyl) 2,2 dichloro 3 ethyl- 4,5-imidazolidinedione.

4. 1 phenylsulfonyl 2,2 dichloro 3 n butyl 4,5- imidazolidinedione.

5. 1 phenylsulfonyl 2,2 dichloro 3 ethyl 4,5- imidazolidinedione.

6. 1 [(4 chlorophenyl)sulfony1] 2,2 dichloro 3-n-propyl-4,S-imidazolidinedione.

7. 1 [(4 chlorophenyDsulfonyl] 2,2 dichloro 3-n-butyl-4,5-imidazolidinedione.

8. 1 methylsulfonyl 2,2 dichloro 3 n prowl-4,5- imidazolidinedione 9. A1-substituted-2,2-dialkoxy-4,S-imidazolinedione of the formula:

RIIO RI! wherein R is selected from the group consisting of alkyl offrom 1 to 6 carbon atoms, inclusive, cycloalkyl of from to 8 carbonatoms, inclusive, phenyl, alkylphenyl wherein the alkyl is defined asabove, p-chlorophenyl, pacetylphenyl, p-alkoxyphenyl, m-alkoxyphenyl,and p,mdialkoxyphenyl in which the alkyl of the alkoxy group is definedas hereinabove, wherein R is selected from the group consisting of alkylof from 2 to 8 carbon atoms, inclusive, cycloalkyl defined as above, andhexame-thyleneirnino, and wherein R" is alkyl of from 1 to 4 carbonatoms, inclusive.

References Cited UNITED STATES PATENTS 3,069,466 12/1962 Pantlitschko260-553 3,097,241 7/1963 Korger et al 260553 3,105,006 9/1963 Wright260-553 3,121,102 2/1964 Tull et a1. 260553 FOREIGN PATENTS 1,305,7238/1962 France.

OTHER REFERENCES The Merck Index 7th ed., p. 183, Rahway, N.J., Merck,1960.

Stachel, Angewandte Chemie, vol. 71, p. 246 (1959).

JOHN D. RANDOLPH, Primary Examiner.

WALTER A. MODANCE, Examiner.

NATALIE TROUSOF, Assistant Examiner.

